Acromegaly is hormone disorder resulted from excess growth hormone secreted by pituitary gland caused by hypophysial adenoma, etc., and bones and soft tissues of head and limbs of patients with acromegaly are swell. Although acromegaly is not always a disease with high prevalence, which is approximately 60 per 1 million people, but it's a serious disease which increases the risk of death because the patients are interfered with their daily life by abnormality of parts of their body, and also one thirds of them have heart disease.
As treatment for the patients with acromegaly, along with an operation to remove adenoma which secrete growth hormone surgically or radiotherapy, there are medical therapies, etc., wherein somatostatin analogs, which are hormones to suppress the secretion of growth hormone, are administered extrinsically. As these somatostatin analogs like this, there are Novartis Pharmaceuticals's Octreotide acetate (Sandostatin®) and Ipsen Pharma's Lanreotide acetate (Somatuline® LA), and effectiveness of them are confirmed. However, these medicines need to be taken by injection because they are peptidic medicines, and the patients reportedly suffer a lot of pain when its prolonged release preparation is administered by intramuscular injection to them once a several weeks. To solve the problem, it would appear that non-peptidic, low-molecular compound which can be administered orally is the best choice rather than the peptidic medicines which need to be administered by injection.
On the other hand, there are 5 subtypes, SSTR1 to SSTR5, identified so far as somatostatin receptors, said Octreotide acetate and Lanreotide acetate are reported to bind to somatostatin receptor subtype 2 (SSTR2) with high affinity. Moreover, they are reported to bind to somatostatin receptor subtype 3 (SSTR3) and somatostatin receptor r subtype 5 (SSTR5) with moderate affinity and not to bind somatostatin receptor subtype 1 (SSTR1) and somatostatin receptor subtype 4 (SSTR4).
As the difference of affinity of Octreotide acetate and Lanreotide acetate against these receptor subtypes become clearer scientifically, some non-peptidic, low-molecular weight compounds are synthesized as somatostatin receptor agonists.
For example, it is mentioned that the compounds represented by the general formula (A):
[wherein
BA and DA represent independently carbon or nitrogen, AA and FA represent independently CH or nitrogen, but only one or two among AA, BA, DA and FA are nitrogen simultaneously;
R1A and R1aA represent independently hydrogen or C1-12 alkyl, etc.;
R2A represents hydrogen or C1-12 alkyl, etc.;
R5A and R4A represent independently hydrogen, halogen or C1-12 alkyl, etc.;
R5A represents (CH2)mAC6-10 aryl or (CH2)mAC5-10 heterocyclyl;
R6A represents hydrogen, halogen or CN, etc.;
R7A represents hydrogen, halogen or C1-6 alkyl, etc.;
mA is an integer of 0 to 6;
xA is an integer of 1 to 3.]
and a pharmaceutically acceptable salt thereof, an ester thereof, an enantiomer thereof and a mixture thereof (definitions of each groups are excerpted) are SSTR2 selective agonists and they are useful for medical treatment of diabetic or related lesions (retinopathy, neurological disorder and nephropathy, etc.) in Patent Literature 1.
Alternatively, it is mentioned that the compounds represented by the formula (B):
have SSTR agonist activity, depresses growth hormone secretion by systemic administration and inhibits angiogenesis of eyes by local administration in Non-Patent Literature 1.
Additionally, it is mentioned that the compounds represents by the general formula (C):
[wherein
R1C represents straight or branched (C1-C16) alkyl group, alkenyl group or alkynyl group etc;
R2C represents a group described by —C(YC)NHX1C, —C(O)X2C, or —SO2X3C;
YC represents oxygen or sulfur;
R3C represents hydrogen, alkyl group which may be substituted, alkenyl group, alkynyl group, aralkyl group which may be substituted, or heteroaryl alkyl group which may be substituted, etc.;
X1C represents straight or branched (C1-C15) alkyl group, alkenyl group or alkynyl group;
X2C represents alkenyl group, etc. which may be substituted with straight or branched (C1-C10) alkyl group or phenyl;
X3C represents alkenyl group, etc. which may be substituted with straight or branched (C1-C10) alkyl group or phenyl]
and a pharmaceutically acceptable inorganic or organic acid salt thereof (the definition of each groups are excerpted) show good affinity with somatostatin receptor and especially useful for medical treatment for the pathological state and diseases related with somatostatin receptor in Patent Literature 2.
And it is mentioned that the 3-thio-1,2,4-triazole compound represented by the formula (D) below:
is SSTR2 and SSTR5 agonist in Non-Patent Literature 2.
However, the present invention compounds represented by the general formula (I) described below, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof and medical use thereof are not shown in any prior art, and are not followed from any combination of them.